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The synthesis of multigram quantities of small molecule PCSK9 inhibitor (R,S)-3is described. The route features a safe, multikilogram method to prepare 5-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2H-tetrazole (10). A three-component dynamic kinetic resolution between tetrazole 10, acetaldehyde, and isobutyric anhydride was catalyzed by a chiral DMAP catalyst to afford enantiomerically enriched hemiaminal ester (S)-12on multikilogram scale. Magnesiation, transmetalation, and Negishi coupling provided access to Boc-intermediate (R,S)-13, which was deprotected to provide (R,S)-3in multigram quantities.

Abstract:Ruination has recently received much attention as a defining aspect of the materiality of modernity. Less attention is given to the processes of regeneration that occur within sites of ruination. In this article, we examine how processes of ruination and regeneration are folded into each other, by looking at the materiality of a single site, a small village in the vicinity of Dakar, Senegal. By building the University of the African Future at Sébikotane, the Senegalese president has sought to rekindle the spirit of excellence that inspired education at the École normale William Ponty in a Pan-African spirit. As part of a larger plan for urban expansion, the site of Sébikotane has inspired hope for development. Examining how the different temporalities of utopian modernism and Afro-nostalgia intersect in the ruined site, this article reflects on the ruination of African futures on a site of ever renascent utopian infrastructures.Résumé:Si les ruines sont souvent décrites comme un élément clé de la modernité dans son aspect matériel, on prête moins attention aux processus de régénération qui peuvent avoir lieu sur leurs sites. Ici nous examinerons les processus de ruines et de régénération dans leurs entrelacements en nous penchant sur un site particulier : un petit village aux alentours de Dakar, au Sénégal. En construisant l'Université du Futur Africain à Sébikotane, le président sénégalais tentait de réanimer, dans une logique panafricaine, l'esprit d'excellence qui avait inspiré l'éducation fournie àl'École normale William Ponty. Dans le cadre d'un plan d'expansion urbaine plus étendu, le site de Sébikotane inspire aujourd'hui de nouveaux espoirs de développement. En examinant le croisement de diverses temporalités de modernisme utopique et d'Afro-nostalgie présentes sur ce lieu en ruines, nous porterons une réflexion sur les ruines des futurs africains, interposées entre des infrastructures utopiques toujours renaissantes.

AbstractRuination has recently received much attention as a defining aspect of the materiality of modernity. Less attention is given to the processes of regeneration that occur within sites of ruination. In this article, we examine how processes of ruination and regeneration are folded into each other, by looking at the materiality of a single site, a small village in the vicinity of Dakar, Senegal. By building the University of the African Future at Sébikotane, the Senegalese president has sought to rekindle the spirit of excellence that inspired education at the École normale William Ponty in a Pan-African spirit. As part of a larger plan for urban expansion, the site of Sébikotane has inspired hope for development. Examining how the different temporalities of utopian modernism and Afro-nostalgia intersect in the ruined site, this article reflects on the ruination of African futures on a site of ever renascent utopian infrastructures.

AbstractCharacterisation of tumours on imaging is usually performed qualitatively by visual analysis by radiologists. However, incorporating quantitative imaging features would potentially increase diagnostic accuracy and would improve patient care and management. The goal is to eventually be able to distinguish certain quantifiable features, which along with qualitative ones could differentiate between benign and malignant tumours. This may obviate the need for invasive procedures such as a biopsy, and may also allow for earlier detection as well as better follow-up. The shape of a tumour is often qualitatively described to help differentiate between tumor types. A smooth round outline is generally thought to be indicative of a benign or slowly growing lesion. A malignant neoplasm, on the other hand, tends to have disorganised growth and has a lobulated or spiculated margin. In this manuscript, we introduce a new computed tomography-based pipeline for tumour analysis and characterisation. This method yields an easily interpretable histogram-based index of lobularity. The EdgeRunner Pipeline performs equally well in studies of individual subjects, or in population-based assessments. Importantly, the methods can be easily translated to clinical use.

Several density separation techniques using numerous brine solutions have been developed for the separation of microplastics from sediment. The aim of this study was to validate the use of various brine solutions in a relatively rapid, reproducible, low cost single stage method that can deliver consistently high recoveries for different microplastic polymers <1 mm appropriate for monitoring programmes. The recovery of environmentally relevant microplastics (200–400 μm and 800–1000 μm) from post-consumer products was tested against tap water and brine solutions of varying density including sodium chloride (NaCl), sodium bromide (NaBr), sodium iodide (NaI) and zinc bromide (ZnBr2). As expected a general trend of increasing microplastic recovery with increasing solution density was observed, with NaI and ZnBr2having significantly (p≤ 0.001) higher rates of microplastic recovery. Microplastic size was found to influence recovery rates and needs to be taken into consideration when choosing a brine solution. From this work it is evident that density separation recovery tests are needed to validate the use of brine solutions for microplastic recovery and that ZnBr2is a novel and appropriate brine solution for microplastic extraction. This study represents the most in depth validation of brine solutions for the density separation of microplastic from sediments undertaken to date.

Microplastics are considered to be a widespread environmental contaminant. Due to their small size microplastics have the potential to be ingested by a range of aquatic organisms which mistake them for a food source and can suffer adverse impacts as a result. Development of standardised methods is imperative to provide reliable and meaningful data when analysing microplastic ingestion by marine fauna. A range of proteolytic digestive enzymes (trypsin, papain and collagenase) were tested to establish optimum digestion efficacy of biological samples and assess the effects of enzymes on microplastics; additionally the applicability of freezing and formaldehyde followed by ethanol as specimen preservation techniques for microplastic research was investigated. Of the enzymes investigated, trypsin yielded the greatest digestive efficacy based on weight reduction (88% ± 2.52 S.D.) at the lowest concentration (0.3125%) with no observed impacts on microplastics. Enumeration of microplastics from wild collected Mytilus edulisrevealed mean numbers of 1.05 ± 0.66 S.D. (minimum) to 4.44 ± 3.03 S.D. (maximum) microplastic particles per g wet weight mussel tissue depending on location. There was no significant difference based on preservation method on the quantification of ingested microplastics and no detrimental impacts were observed on the microplastics directly. Enzymatic digestion using trypsin therefore provides a suitable, time and cost effective method to extract microplastics from M. edulis. Furthermore the preservation methods did not have detrimental effects on microplastics, serving to highlight the suitability of biological samples preserved either way for future inquiries into ingested microplastics.

Introduction:Machine learning techniques can predict operational capacity needs and improve understanding of procedural risk in heterogeneous patient populations. Our goal is to combine machine learning and computer simulation to design scheduling formats for pediatric cardiac catheterization maximizing patient safety and system efficiency.Methods:Data for 13,115 pediatric cardiac catheterizations from 2010-19 were used to develop a simulation model including 3 catheterization interventional laboratories. Data on case time, patient and procedural complexity, and adverse events were used to determine statistical distributions on patient, procedure, and system factors for key components of the catheterization lab process. The simulation model was used to evaluate scheduling plans implemented for historical and synthetic populations of patients, comparing both system efficiency and total lab time spent where the system risk of an adverse event is high.Results:A simple scheduling heuristic model was developed where one lab worked cases from lowest to highest risk and another lab worked from highest to lowest risk. This scheduling heuristic was applied to all cases in 2018 and compared against the original schedule. Using thresholds of 10% and 20% probability of an adverse event to separate low, medium- and high-risk times. Implementing the sorting schedule resulted in the reduction of minutes spent at high-risk equivalent to 11.57 days per year.Conclusions:This study demonstrates that predictive analytics and simulation using simple scheduling heuristics results in reduced time at increased risk. Future work includes improving the fidelity of the model to include specific providers, case cancellations, and other system complexities.

Purpose: This paper aims to examine how media play a role in community responses to disaster. The authors explore how communication technology may allow new relationships between community groups and emergency agencies. The authors examine the context within which warnings and risk communication are interpreted by media services. The authors observe how, in an emergency context, the thinking about media may change from that of a linear framework of information provision to one of shared resources. Design/methodology/approach: The authors focus on Second Life, a shared, online space which uses 3D graphic images to simulate a virtual environment. Second Life is posited as a media tool with clear advantages for the training of emergency services professionals and citizens in the community. The authors observe emergency training scenarios and advantages for training for critical thinking and decision-making. Findings: The authors observe then how virtual worlds such as Second Life provide an online forum in which participants can interact, communicate and simulate action in a complex 3D graphic environment. Second Life may be a useful medium for simulating and testing geo-physical and social manoeuvres using the modeling tools. This may allow for collaborative decision-making in simulations which can prepare or rehearse people for emergency conditions. It may be useful in an emergency with information streamed and coordinated at a single online site. A shared network like Second Life may be shared by many people co-synchronously or a-synchronously, despite their geographic distance. Second Life applications may also be useful in the aftermath of emergencies for design and rebuilding, for analytical and educational purposes. Research limitations/implications: It is clear that social networks like Second Life provide a valuable tool with which to learn about and share data and information about bushfires, community emergencies and safety precautions in a social setting. It can also provide, at the local level, a forum for community information and discussion, as well as for counselling and reconstruction in the aftermath. Practical implications: The authors suggest that the range and flexibility of tools and their excellent geographic visualization and social networking functions may in future allow for learning and decision-making among diverse and disparate groups who can come together in virtual space. It is especially useful in remote communities as a means of uniting people who are otherwise isolated by distance or trapped in emergency situations. Second Life is useful for sharing information, organizational and local knowledge about disaster and mitigation management. This media-rich platform is valuable to a community that is increasingly adept with shared, 3D graphic computer interfaces. Social implications: Applications like Second Life may provide a space where users can access a range of tools as a means of informing, educating, empowering and warning participants in emergency scenarios, both real and simulated. They are more than virtual spaces; they are also social spaces. A platform like Second Life may provide a virtual solution for such communication challenges especially where communities are too remote, too dispersed or even too many in number to be easily accessible in the field. Originality/value: This paper contains new and significant information about emerging communication systems and platforms that may be of use to those researching and planning around disaster management, mitigation and resilience. It addresses the use of new techniques which are the result of innovation in technology, software design and network design. It applies a discussion of these techniques to several hypothetical and real-life scenarios to explore the potential for virtual tools as a way of providing enriched information, mapping and communication tools across a range of disaster response scenarios.

Objective: The psychiatric emergency room is a dynamic and sometimes volatile environment. Its design may be an important variable in patient care, but most design decisions are based on models of thought and treatment with a minimal evidence base.Background: The concept of open design, increasing access of patients to nursing staff, for inpatient psychiatric units has recently gained widespread acceptance, despite a dearth of empirical data.Methods: We examined rates of seclusion and restraint before and after a design change that reduced the openness of the unit in a dedicated emergency psychiatric service in a general university hospital. Quality assurance data regarding the census, occurrence of assaults, and the use of seclusion and restraint were queried. Two independent analyses utilizing a test of proportional data were performed to replicate the findings.Results: After placement of a door to restrict patients’ access to the waiting area of the unit, the rate of the use of seclusion and restraint went from 0.03 (44/777) to 0.0185 (27/1,514; z= 2.02, p< .04). Replication over a separate time period saw reduction from 0.029 (67/2,277) to 0.018 (44/2,431), z= 2.44, p< .02).Conclusion: A design change that reduced the openness of the unit resulted in the reduction of seclusion and restraint.

The behaviour of dry, moist, and saturated soils has been studied for over a century without ade quately investigating the behaviour associated with transient saturation in the near surface, i.e. the upper 1 m of overburden, including the effects of rapid meteorological changes, dynamic fluid flow, and variability of saturation on shallow seismic sensors. This paper presents observational data wherein the geophysical instrumentation response was significantly influenced by near‐surface post‐precipitation saturation and additional laboratory experimentation on the effects of satu ration on shear wave velocity. The lack of partially‐saturated data is primarily because transient meteorological events have not been critically important to the types of long‐term deployments performed in the past, where sensors were situated in hard‐rock, collecting data under idealized conditions, as opposed to sedimentary settings. Shorter‐duration deployments and smaller system architectures, e.g. persistent monitoring, now necessitate detailed a priori knowledge of meteoro logical impacts to system design and performance. The purpose of this persistent monitoring geophysical instrumentation is to continually monitor the near surface and relate small perturbations to a specific source type(s) and distance(s) from the receiver. As such, the received signal is compared to known sources within a predetermined geo logical/meteorological condition. Presented herein is the calibration signal generated by a 3.63‐kg (8‐lb) sledgehammer prior to and post 36 hours of steady precipitation. The resulting subsurface seismic velocity time‐histories show a significant increase in signal amplitude, change in fre quency content and no change in duration. Thus, the amplification effects of near‐surface moisture variability combined with dynamic pore fluid could be interpreted as false positives of a specific source signature and/or instrument failure.

To measure the volume of basal forebrain septal nuclei in patients with temporal lobe epilepsy (TLE) as compared to patients with extratemporal epilepsy and controls. In animal models of TLE, septal lesions facilitate epileptogenesis, while septal stimulation is antiepileptic.

Observers note a trend of shareholder lawsuits migrating out of Delaware. This trend is a manifestation of a litigation strategy by plaintiffs' counsel to avoid Delaware's aggressive policing of agency costs in acquisition-related shareholder litigation and to gain control over such litigation by bringing these cases outside of Delaware. To the extent agency costs drive acquisition-related litigation, such litigation can be costly to shareholders without much by way of tangible benefits to them. In addition to being potentially wasteful for shareholders, a sustained outward migration of cases from Delaware to other venues may threaten Delaware's ability to maintain and develop its own corporate law. For these reasons, various stakeholders including shareholders, the judiciary, and policymakers, have an incentive to consider the implications of these multiforum litigation strategies and formulate a response. Some commentators have proposed that firms adopt forum selection provisions in their corporate charters and bylaws as a way of reducing incentives for shareholder plaintiffs to engage in wasteful lawsuits or forum shopping. Notwithstanding the fact that incorporators are free to contract around default rules and adopt innovative self-help provisions, few firms have taken that step. This Article argues that insights from behavioral economics can provide some understanding of why this may be the case. In particular, status quo bias in contracting reduces incentives for incorporators to pursue more creative approaches to drafting the corporate contract. However, status quo bias may be overcome through the use of opt-in menus, which have been useful in increasing contractual flexibility in other contexts in corporate law and may prove helpful in overcoming cognitive constraints to innovation. By increasing flexibility in corporate contracts, shareholders should be able to moderate the effects of status quo bias and develop charter terms more likely to reflect their true preferences. Properly structured exclusive forum provisions will reduce incentives to bring wasteful litigation while leaving open opportunities for shareholders to bring valuable lawsuits. [ABSTRACT FROM AUTHOR]

Although observational findings linking breast milk to higher scores on cognitive tests may be confounded by factors associated with mothers' choice to breastfeed, it has been suggested that one or more constituents of breast milk facilitate cognitive development, particularly in preterms. Because cognitive scores are related to head size, we hypothesized that breast milk mediates cognitive effects by affecting brain growth. We used detailed data from a randomized feeding trial to calculate percentage of expressed maternal breast milk (%EBM) in the infant diet of 50 adolescents. MRI scans were obtained (mean age 15 y 9 mo), allowing volumes of total brain (TBV) and white and gray matter (WMV, GMV) to be calculated. In the total group, %EBM correlated significantly with verbal intelligence quotient (VIQ); in boys, with all IQ scores, TBV and WMV. VIQ was, in turn, correlated with WMV and, in boys only, additionally with TBV. No significant relationships were seen in girls or with gray matter. These data support the hypothesis that breast milk promotes brain development, particularly white matter growth. The selective effect in males accords with animal and human evidence regarding gender effects of early diet. Our data have important neurobiological and public health implications and identify areas for future mechanistic study.

Although observational findings linking breast milk to higher scores on cognitive tests may be confounded by factors associated with mothers' choice to breastfeed, it has been suggested that one or more constituents of breast milk facilitate cognitive development, particularly in preterms. Because cognitive scores are related to head size, we hypothesized that breast milk mediates cognitive effects by affecting brain growth. We used detailed data from a randomized feeding trial to calculate percentage of expressed maternal breast milk (%EBM) in the infant diet of 50 adolescents. MRI scans were obtained (mean age = 15 y 9 mo), allowing volumes of total brain (TBV) and white and gray matter (WMV, GMV) to be calculated. In the total group, %EBM correlated significantly with verbal intelligence quotient (VIQ); in boys, with all IQ scores, TBV and WMV. VIQ was, in turn, correlated with WMV and, in boys only, additionally with TBV. No significant relationships were seen in girls or with gray matter. These data support the hypothesis that breast milk promotes brain development, particularly white matter growth. The selective effect in males accords with animal and human evidence regarding gender effects of early diet. Our data have important neurobiological and public health implications and identify areas for future mechanistic study.

From 2001 to 2008, the Robert Wood Johnson Foundation funded the Economic Research Initiative on the Uninsured (ERIU), housed at the University of Michigan. The goals of ERIU were to increase, diversify, and improve the quality and quantity of economics research on the uninsured, and to translate that research into the type of resources that are useful to policymakers, policy analysts, researchers, and members of the media.One of the primary objectives of ERIU was to fund research projects that explored economic issues about the uninsured in new, yet rigorous and interesting ways. ERIU began by commissioning six critical syntheses of the existing research. These syntheses were intended to inform researchers of what we know and what we don't know about the uninsured. In eight years, ERIU funded more than 50 new research projects on a variety of coverage topics aimed at addressing the gaps in knowledge highlighted in these syntheses. These projects, involving more than 100 researchers, resulted in over 70 conference and seminar presentations worldwide and approximately 40 articles published in peer-reviewed journals.

Candidate kairomones of ornithophilic mosquito species are reported from GC/MS analysis of compounds from the skin on the back, the feet, and feathers from the back of White Leghorn chickens (Gallus gallus domesticus). Hexane and ether extracts of chicken feathers differ significantly in attractiveness of Culex spp. mosquitoes. The active (hexane) extracts contained an abundance of alcohols, ketones, and diones. The inactive (ether) extracts contained aldehydes, which also were in the hexane extracts. Analysis of hexane extracts from chicken feet, skin, and feathers demonstrated the qualitative similarity in the compounds collected with subtle differences observed in the quantitative amounts of these compounds. Aldehydes and carboxylic acids were detected in a concentrated ether extract of feathers in quantitatively similar ratios within each compound class for the corresponding series of C6–C9 aldehydes and acids.

Early nutrition in animals affects both behavior and brain structure. In humans, randomized trials show that early nutrition affects later cognition, notably in males. We hypothesized that early nutrition also influences brain structure, measurable using magnetic resonance imaging. Prior research suggested that the caudate nucleus may be especially vulnerable to early environment and that its size relates to IQ. To test the hypothesis that the caudate nucleus could be a neural substrate for cognitive effects of early nutrition, we compared two groups of adolescents, assigned a Standard- or High-nutrient diet in the postnatal weeks after preterm birth. Groups had similar birth status and neonatal course. Scans and IQ data were obtained from 76 adolescents and volumes of several subcortical structures were calculated. The High-nutrient group had significantly larger caudate volumes and higher Verbal IQ (VIQ). Caudate volumes correlated significantly with VIQ in the Standard-nutrient group only. Caudate volume was influenced by early nutrition and related selectively to VIQ in males, but not in females. Our findings may partly explain the effects of early diet on cognition and the predominant effects in males. They are among the first to show that human brain structure can be influenced by early nutrition.

Early nutrition in animals affects both behavior and brain structure. In humans, randomized trials show that early nutrition affects later cognition, notably in males. We hypothesized that early nutrition also influences brain structure, measurable using magnetic resonance imaging. Prior research suggested that the caudate nucleus may be especially vulnerable to early environment and that its size relates to IQ. To test the hypothesis that the caudate nucleus could be a neural substrate for cognitive effects of early nutrition, we compared two groups of adolescents, assigned a Standard- or High-nutrient diet in the postnatal weeks after preterm birth. Groups had similar birth status and neonatal course. Scans and IQ data were obtained from 76 adolescents and volumes of several subcortical structures were calculated. The High-nutrient group had significantly larger caudate volumes and higher Verbal IQ (VIQ). Caudate volumes correlated significantly with VIQ in the Standard-nutrient group only. Caudate volume was influenced by early nutrition and related selectively to VIQ in males, but not in females. Our findings may partly explain the effects of early diet on cognition and the predominant effects in males. They are among the first to show that human brain structure can be influenced by early nutrition.

Background: Previous work showed that piperazinyl-cross-linked ciprofloxacin dimer exhibits good bacteriostatic activity with Streptococcus pneumoniae and Staphylococcus aureus; lethal activity was not measured. Subsequently, the dimer failed to kill Mycobacterium smegmatis but blocked growth. Whether the compound is lethal with non-mycobacterial species is not known.Methods: Bacteriostatic and bactericidal activities were measured with wild-type cells and topoisomerase mutants of S. aureus and Escherichia coli for ciprofloxacin and a dimer of ciprofloxacin. Spontaneous resistance mutants were selected with S. aureus for both compounds, followed by target identification by nucleotide sequence determination of the quinolone-resistance-determining-region of gyrA (gyrase) and parC (topoisomerase IV).Results: The dimer was lethal, in some cases exhibiting more activity than ciprofloxacin (particularly with wild-type cells and a parC mutant of S. aureus). Dimerization affected target preference with S. aureus but not with E. coli. Resistance mutations in either gyrA or parC of S. aureus raised the MIC of the dimer, but only a parC mutation raised the MIC of ciprofloxacin. With S. aureus, the dimer selected spontaneous resistant gyrA mutants, whereas ciprofloxacin selected a parC mutant. With E. coli, a gyrA, but not a parC, mutation raised the MIC of both compounds.Conclusion: The dimer readily killed S. aureus and E. coli, representative Gram-positive and Gram-negative bacteria. In both cases the preferred target was DNA gyrase. The switch in target preference may be responsible for the greater lethality of the dimer seen with S. aureus.

The reversibility and regression of histological and biochemical findings in a mouse model of Gaucher disease (4L/PS-NA) was evaluated using a liver-enriched activator protein promoter control of a tetracycline-controlled transcriptional activation-responsive human acid {szligbeta}-glucosidase (hGCase) transgenic system. 4L/PS-NA has the acid {szligbeta}-glucosidase (GCase) V394L/V394L (4L) point mutation combined with hypomorphic (∼6% wild-type) expression of the mouse prosaposin transgene (PS-NA). The hGCase/4L/PS-NA had exclusive liver expression of hGCase controlled by doxycycline (DOX). In the absence of DOX, hGCase was secreted from liver at levels of ∼120 µg/ml serum with only ∼8% of full activity, following exposure to pH 7.4 in serum. The hGCase activity and protein were detected in cells of the liver (massive), lung, and spleen, but not the brain. The visceral tissue storage cells and glucosylceramide (GC) accumulation in hGCase/4L/PS-NA were decreased from that in 4L/PS-NA mice. Turning off hGCase expression with dietary DOX led to reaccumulation of storage cells and of GC in liver, lung, and spleen, and macrophage activation in those tissues. This study demonstrates that conditionally expressed hGCase supplemented the existing mutant mouse GCase to control visceral substrate accumulation in vivo.

The reversibility and regression of histological and biochemical findings in a mouse model of Gaucher disease (4L/PS-NA) was evaluated using a liver-enriched activator protein promoter control of a tetracycline-controlled transcriptional activation-responsive human acid β-glucosidase (hGCase) transgenic system. 4L/PS-NA has the acid β-glucosidase (GCase) V394L/V394L (4L) point mutation combined with hypomorphic (∼6% wild-type) expression of the mouse prosaposin transgene (PS-NA). The hGCase/4L/PS-NA had exclusive liver expression of hGCase controlled by doxycycline (DOX). In the absence of DOX, hGCase was secreted from liver at levels of ∼120 μg/ml serum with only ∼8% of full activity, following exposure to pH 7.4 in serum. The hGCase activity and protein were detected in cells of the liver (massive), lung, and spleen, but not the brain. The visceral tissue storage cells and glucosylceramide (GC) accumulation in hGCase/4L/PS-NA were decreased from that in 4L/PS-NA mice. Turning off hGCase expression with dietary DOX led to reaccumulation of storage cells and of GC in liver, lung, and spleen, and macrophage activation in those tissues. This study demonstrates that conditionally expressed hGCase supplemented the existing mutant mouse GCase to control visceral substrate accumulation in vivo.